Abstract The goal of our research program is to determine molecular mechanisms whereby extracellular signals regulate adipocyte differentiation and metabolism. In the past funding period, we have performed novel studies demonstrating an important role for Wnt10b signaling as an inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. Our studies have demonstrated that Wnt10b is expressed in preadipocytes and stromal vascular cells and that Wnt10b decreases rapidly upon induction of adipogenesis. Wnt10b blocks adipogenesis by inhibiting expression of C/EBPa and PPAR?, and neutralization of endogenous Wnt10b with antisera stimulates adipogenesis of preadipocytes. Transgenic mice expressing Wnt10b in adipose tissue (FABP4-Wnt10b) have ~50% less total body fat and a ~60% reduction in visceral fat depots. FABP4-Wnt10b mice are resistant to diet-induced and genetic-obesity, and these mice are more glucose-tolerant and insulin-sensitive than controls. Our studies have expanded the role for Wnt10b from simple inhibition of preadipocyte differentiation to modulating fate of multipotent stem cells. Thus, FABP4-Wnt10b mice not only have less adipose tissue, but they have a four-fold increase in trabecular bone. In addition to a direct effect of Wnt10b to stimulate osteoblastogenesis and decrease adipogenesis of resident mesenchymal progenitor cells in marrow, increased osteoblast activity also appears to be mediated by a novel mechanism through mammalian target of rapamycin and protein translation. Further support for a critical role for Wnt10b in governing fate of mesenchymal precursors comes from our observations that Wnt10b -/- mice have ~30% less trabecular bone and a corresponding decrease in serum osteoblast markers. While our focus to date has been on how Wnt/[unreadable]-catenin influences developmental processes, our preliminary studies suggest that Wnt signaling has additional roles in metabolism. These studies have led us to hypothesize that Wnt signaling is important for regulation of adipocyte and whole body metabolism. The experiments proposed in this application will systematically build on our past studies to understand in greater detail the molecular, cellular and whole animal biology of Wnt signaling.